Summary This application proposes advances to precision medicine along three complementary arcs, building on our initial work in RO1-MH099003 (Characterizing Placebo Response to Active Treatment Using Very High-Dimension- al Data). A primary component of precision medicine involves determining optimal treatment decisions using baseline variables. We have previously developed statistical models that can accommodate both scalar and functional predictors in determining treatment decision functions. This renewal application addresses the fact that available data modalities continue to evolve and grow ever more complex. Determining treatment deci- sions is closely related to the problem of quantifying the degree to which individual outcomes are due to spe- cific drug effects versus placebo responses. We propose to develop completely nonparametric distance-based approaches with the goal of determining optimal treatment decisions and generalizing these to accommodate multiple data modalities. Because no single biomarker for response to treatment has been identified, methods to form composite biomarkers by combining predictors will be developed to incorporate data arising from com- plex modalities. Many brain-related measures are expensive and time consuming to collect, and thus a vital component of optimizing treatment decisions is to develop a sequential treatment decision strategy whereby easy-to-make measurements are obtained first, and the more expensive and time consuming measurements are only obtained if they are needed to improve confidence in a treatment decision. A complementary arc of the proposed research involves stratified psychiatry and developing directed partitioning/clustering methods to improve precision medicine. This is not only important to the work on deter- mining optimal treatment decisions, but also towards a data-driven discovery of psychiatric biotypes. Optimizing treatment decisions is naturally related to the thorny problem of making a clear diagnosis, especially in mental health where there is a wide degree of heterogeneity and overlap in current disease phenotypes. This research aims to expand the notion of endophenotypes from genetics to data modalities based on brain structure, func- tion, and integrity. Specific to this application, the notion of endophenotypes will be expanded to discover more stable phenotypes using biomedical technologies, that those obtained based on symptoms. The Establishing Moderators & Biosignatures for Antidepressant Response in Clinical Care (EMBARC; U01MH092221, U01MH092250 ) study, which is the most ambitious systematic effort to discover biomarkers to guide treatment of major depressive disorder, has collected and made publicly available an unprecedented collection of clinical and biological patient phenotypes. This is a proposal to develop analytic methodology that would be able to take full advantage of rich and complex patient data as those in the EMBARC study for the purposes of precision medicine, in an anticipation of future similar or even more ambitious studies.